Optically pure D,E ring intermediates useful for the synthesis of camptothecin and camptothecin analogs

ABSTRACT

Processes for making compounds of Formulae XIV, XV, and XVII ##STR1## wherein R 6  is lower alkyl, R 7  is lower alkyl, R is lower alkyl, Y is H, F or Cl, R 8  is a compound of Formula XVIII ##STR2## wherein n is 1, 2, or 3, R 11  is C 1  -C 4  alkyl and R 12  is the same as R 11 , or R 11  and R 12  together form cyclopentane or cyclohexane, and R 13  is: 
     (a) phenyl substituted 1 to 5 times with C 3  -C 7  secondary alkyl or C 4  -C 7  ; tertiary alkyl, or 
     (b) selected from the group consisting of naphthyl, anthryl, and phenanthryl optionally substituted 1 to 5 times with C 3  -C 7  secondary alkyl or C 4  -C 7  tertiary alkyl groups, 
     R 10  is C 6  -C 10  alkyl, aryl or alkyl aryl, 
     and Y is H, F or Cl, 
     are disclosed. These processes can be used to make optically enhanced and optically pure forms of the compounds, which are useful in the making of camptothecin and analogs thereof.

RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.07/900,650, filed Jun. 18, 1992, now U.S. Pat. No. 5,212,317, which is acontinuation-in-part of Ser. No. 07/632,970, filed. Dec. 20, 1990 nowU.S. Pat. No. 5,162,532.

FIELD OF THE INVENTION

The present invention provides a parallel synthesis of camptothecin andcamptothecin analogs via novel intermediates at high yields.

BACKGROUND OF THE INVENTION

Camptothecin (Chem. Abstracts Registry No. 7689-03-4) is a naturallyoccurring compound found in Camptotheca acuminata (Nyssaceae) which hasantileukemic and antitumor properties. Numerous camptothecin analogshaving like properties are known, examples being those described in U.S.Pat. No. 4,894,456 to Wall et al. and European Patent Application No. 0325 247 of Yaegashi et al.

A number of synthesis for camptothecin are known. Several routes arereviewed in Natural Products Chemistry, Vol. 2, 358-361 (K. Nakanishi,T. Goto, S. Ito, S. Natori and S. Nozoe eds.) and in J. Cai and C.Hutchinson, Camptothecin, in The Alkaloids, Vol XXI, 101-137 (AcademicPress 1983). The biosynthesis of camptothecin is described in NaturalProducts Chemistry Vol. 3, 573-574 (K. Nakanishi et al. eds.). A recentsynthetic route is described in U.S. Pat. No. 4,894,456 to Wall et al.(see also references cited therein).

A problem with prior methods of synthesizing camptothecin is that theyare largely linear syntheses. Such syntheses provide low yields of thefinal product because of the sequential loss in product during each stepof the total synthesis. Parallel syntheses (i.e., a strategy in whichtwo synthetic paths are followed separately and the products thereofcombined to form the final product) provide higher yields, but few suchsyntheses have been available for camptothecin. Accordingly, an objectof the present invention is to provide a parallel synthetic method formaking camptothecin and analogs thereof.

SUMMARY OF THE INVENTION

The present invention provides a process for making compounds ofFormulae XIV, XV, and XVII below: ##STR3## wherein R₆ is lower alkyl, R₇is lower alkyl, R is lower alkyl, Y is H, F or Cl, R₈ is a compound ofFormula XVIII ##STR4## wherein n is 1, 2, or 3, R₁₁ is C₁ -C₄ alkyl andR₁₂ is the same as R₁₁, or R₁₁ and R₁₂ together form cyclopentane orcyclohexane, and R₁₃ is

(a) phenyl substituted 1 to 5 times with C₃ -C₇ ; secondary alkyl or C₄-C₇ tertiary alkyl, or

(b) selected from the group consisting of naphthyl, anthryl, andphenanthryl optionally substituted 1 to 5 times with C₃ -C₇ secondaryalkyl or C₄ -C₇ tertiary alkyl groups,

R₁₀ is C₆ -C₁₀ alkyl, aryl or alkyl aryl,

and Y is H, F or Cl.

These compounds are useful in the production of compounds of FormulaIII, ##STR5## wherein R and Y are as defined above, which in turn isuseful in the production of compounds of Formula I. ##STR6## wherein:

R may be loweralkyl,

R₁ may be H, loweralkyl, loweralkoxy, or halo,

R₂, R₃, R₄, and R₅ may each independently be H, amino, hydroxy,loweralkyl, loweralkoxy, loweralkylthio, di(loweralkyl)amino, cyano,methylenedioxy, Formyl, nitro, halo, trifluoromethyl, amninomethyl,azido, amido, hydrazino, or any of the twenty standard amino acidsbonded to the A ring via the amino-nitrogen atom (numbering in Formula Iis by the Le Men-Taylor numbering system and rings are lettered in theconventional manner. See J. Cai and C. Hutchinson, supra at 102).

In one embodiment illustrated by Scheme D, ##STR7## R₈ is opticallypure, which can lead to a diastereomerically enhanced compound XIV andoptically enhanced compounds XV, III, and I. In another embodimentillustrated by Scheme E, ##STR8## the use of optically pure R₈ can leadto a diastereomerically pure compound XVII, which in turn can be used toproduce diastereometrically pure forms of compound XV and optically pureforms of compounds III and I.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "loweralkyl" means a linear or branched alkylgroup with 1-8, preferably 1-4, carbon atoms, such as methyl, ethyl,propyl, isopropyl, n-butyl, tert-butyl, hexyl, and octyl. Thisdefinition also applies to a loweralkyl moiety in the loweralkoxy,loweralkylthio, and di(loweralkyl)amino groups. Thus, examples ofloweralkoxy groups are methoxy, ethoxy, propoxy, sec-butoxy, andisohexoxy; examples of loweralkylthio groups are methylthio, ethylthio,tert-butylthio, and hexylthio; and examples of di(loweralkyl)aminogroups are dimethylamino, diethylamino, diisopropylamino,di(n-butyl)amino, and dipentylamino.

The terms "halo" and "halogen" as used herein refers to a substituentwhich may be fluoro, chloro, bromo, or iodo.

Substituents on the "A" ring of the compounds disclosed herein may bejoined together to form a bifunctional substituent such as themethylenedioxy group. Methylenedioxy substituents may be bonded to anytwo consecutive positions in the A ring, for example, the 9,10, the10,11, or the 11,12 positions.

Substituents which are standard amino acids may be any of the twentyamino acids commonly found in naturally occurring proteins, and are wellknown in the art. These provide a substituent of the formula -NHCHRCOOH,with R being the side chain of any of the twenty standard amino acids.The amino acids may be of any configuration, but preferably have an (L)configuration.

A compound of Formula I is produced in accordance with Scheme A below byalkyating a pyridone of Formula III with a chloromethylquinoline ofFormula II to produce a compound of Formula IV, and then cyclizing thecompound of Formula IV to yield the compound of Formula I. ##STR9##

In Scheme A: Y is H; R and R₁ through R₅ are as given in connection withFormula I above; X is halogen, preferably bromo or iodo; and W ishalogen, preferably chloro.

The starting materials of Scheme A, the compounds of Formula II and III,are prepared in accordance with Schemes B and C, D, or E below.

The pyridone of Formula III may be alkylated with a halomethylquinolineof Formula II in a suitable solvent, such as a polar protic solvent(e.g. isopropyl alcohol, ethanol, methanol), an aprotic solvent (e.g.,1,2-dimethoxyethane, tetrahydrofuran, toluene, acetonitrile, ordimethylformamide) or alternatively in an aqueous solution in thepresence of a phase transfer catalyst. The reaction is preferablycarried out under mildly basic conditions, to minimize attack on thepyridone ring oxygen. The reaction may be carried out as a single step,or may conveniently be carried out in two stages by, first, forming theanion of the pyridone by addition of an alkali earth salt (e.g.,potassium tert-butoxide) at about room temperature, and then adding thehalomethylquinoline to the reaction solution and heating the solutionbetween about 60° to about 100° Centigrade for 4-24 hours.

The compound of Formula IV may be cyclized to yield the compound ofFormula I by an intramolecular Heck reaction. The reaction is carriedout in the presence of a palladium catalyst (e.g., palladium acetate)under basic conditions in a polar aprotic solvent such as acetonitrileor dimethylformamide. A phase transfer catalyst such as atetraalkylammonium halide salt is preferably included. The reactionshould be carried out in an inert atmosphere, such as under argon. Thereaction mixture may be heated to a temperature between about 50° toabout 100° C. for about 1 to 24 hours. Variations on these conditionswill be apparent from the literature on the Heck reaction. See, e.g., R.Grigg et al. Tetrahedron 46, 4003-4008 (1990).

The compounds of Formula II may be prepared in accordance with Scheme Bbelow, where R₁ through R₅ are as given in connection with Formula Iabove, and X is bromo or iodo, preferably iodo. ##STR10##

The starting materials in Scheme B, the compounds of Formula V, are madeby known techniques, such as by chlorination of a quinoline. See, e.g.,Progress in Heterocyclic Chemistry 2, 180 (H. Suschitzky and E. Scriveneds. 1990). In the alternative, compounds of Formula V may be made fromthe substituted acetanilide as described by 0. MethCoyn et al., J. Chem.Soc. Perkin Trans. I 1981, 1520.

The halo group on the carboxaldehyde of Formula V is exchanged with aniodo or bromo (preferably iodo) to produce the carboxaldehyde of FormulaVI. The exchange reaction may be carried out in acetonitrile in thepresence of a catalytic amount

of a strong acid, such as HCl, by heating the reaction mixture tobetween about 70° to about 90° C. for at least about 4 hours.

The carboxaldehyde of Formula VI is then reduced to produce thehydroxymethylquinoline of Formula VII. The reaction is carried out witha mild reducing agent to avoid reducing the quinoline ring, at atemperature of from about 0° to about 25° C., in an alcohol solvent. Analternative route for producing a compound of Formula VII is disclosedin N. Narasimham et al., J. Chem. Soc., Chem. Commun., 1985, 1368-1369.

A compound of Formula II is produced from the hydroxymethylquinoline ofFormula VII in accordance with conventional procedures in a solvent inwhich the reactants are soluble, such as dimethylformamide. The reactionis preferably carried out at lower temperatures to provide a higheryield.

The compounds of Formula III above are preferably prepared in accordancewith Scheme C below, wherein R is as given in connection with Formula Iabove, R₆ and R₇ are loweralkyl, preferably methyl, R₈ is loweralkyl,preferably ethyl, Y is Cl or H, and Z is halo, preferably bromo or iodo.##STR11##

The starting materials for Scheme C, the compounds of Formula VIII, maybe prepared in accordance with known techniques. For example, thesynthesis of 2-methoxy-3-pyridinecarboxaldehyde is disclosed in D.Comins and M. Killpack, J. Org. Chem. 55, 69-73 (1990).

In Scheme C, the carboxaldehyde of Formula VIII is halogenated toproduce the 4-halo-3-pyridinecarboxaldehyde of Formula IX. Halogenationat the 4- position may be carried out by reacting the carboxaldehyde ofFormula VIII with a lithiated diamine, such as lithiatedN,N,N'-trimethylethylenediamine, in dimethoxyethane or tetrahydrofuranto protect the aldehyde and direct subsequent C-4 lithiation, and bythen lithiating the C-4 position of the pyridine with a suitablelithiating reagent, such as n-butyllithium. See D. Comins and M.Killpack, supra. The C-4 lithiated pyridine intermediate is preferablyhalogenated by adding the intermediate to a solution of iodine orbromine in a polar or nonpolar organic solvent, preferably at atemperature of at least as low as about -70° C.

The compound of Formula IX is reduced in an alcoholic acidic media inthe presence of a trialkylsilane to yield the alkoxymethylpyridine ofFormula X. The acid should be a strong acid, such as sulfuric ortrifluoroacetic acid. At least about 2 molar equivalents of a suitablealcohol (e.g., methanol, ethanol, tert-butanol]should be included toconvert the aldehyde to the ether. Reference may be made to theliterature on the silane reduction of aldehydes for conditions andvariations on this reaction. See, e.g., M. Doyle et al., J. Am. Chem.Soc. 94:10, 3659-3661 (1972).

The compound of Formula X is lithiated at the C-4 position with alithiating agent such as n-butyllithium, and then reacted with acompound of Formula XI such as an alkyl α-ketobutyrate (e.g., methylα-ketobutyrate, ethyl α-ketobutyrate, tert-butyla-ketobutyrate) toproduce the compound of Formula XII in essentially the manner describedby R. Lyle et al., J. Org. Chem. 38, 3268-3271 (1973). The reaction maybe carried out in a tetrahydrofuran or ether solvent at a temperature ofat least as low as about -50° C., with the alkyl α-ketobutyrate beingadded to the reaction solution as a single aliquot.

The compound of Formula XII is then cyclized to yield the compound ofFormula III. Cyclization may be carried out by reacting the compound ofFormula XII with bromo- or iodotrimethylsilane (preferablyiodotrimethylsilane) in a neutral or polar aprotic solvent such asacetonitrile, followed by reaction with a strong acid solution to cleavethe ethers and yield the compound of Formula III (the ring formingspontaneously upon cleavage of the ethers). The bromo- oriodotrimethylsilane is preferably generated in situ in accordance withknown techniques, such as by the reaction of chlorotrimethylsilane witha halogen salt or elemental halogen. See A. Schmidt, Aldrichimica Acta14, 31-38 (1981).

When Y is halo in the compound of Formula III, the compound may behydrogenated by any suitable technique, preferably by catalytichydrogenation in the presence of a palladium catalyst in a hydrogenatmosphere under pressure (e.g., at least three atmospheres). Seegenerally J. March, Advanced Organic Chemistry, 510-511 (3d. Ed. 1985).

As alternatives to Scheme C, a compound of Formula III, where Y is H,may be prepared in the manner described in D. Comins, Ph.D. Thesis,University of New Hampshire, Durham, NH, at 25-29 (1977), and asdescribed in Lyle et al., J. Org. Chem. 38, 3268-3271 (1973).

Another alternative to Scheme C is Scheme D, shown below, ##STR12##wherein R, R₆, R₇, Y, and Z are as given in connection with Formula IIIabove. R₈ can be any chiral moiety which, because of its geometricconfiguration, directs the nucleophilic substitution of compound XIII bycompound X to preferentially form the tertiary alcohol of compound XIVin one stereochemical orientation over its opposite stereochemicalorientation. R₈ forces a preferential orientation of compound XIV bysterically hindering the formation of the non-preferred diastereomer.Exemplary chiral compounds suitable for use in the process include aryland alkyl aryl compounds optionally substituted from 1 to 5 times withC1-C4 alkyl groups, any of the compounds disclosed in U.S. patentapplication Ser. No. 07/855,721, the subject matter of which is hereinincorporated by reference, 4-phenylmethyl -2 oxazolidine,3-(1-naphthyl)-4,7,7-trimethylbicyclo [2.2.1]heptane, trans-2,5Bis(methoxymethoxy methyl)pyrrolidine, 2,10-camphorsulfamide, N,N-dicylcohexyl-10 camphorsulfamide, proline benzyl ester, pantolactone,and 4-benzyl-Z-oxazolidinone. Preferred chiral auxiliaries are compoundsof the Formula XVIII ##STR13## wherein n is 1, 2, or 3, R₁₁ is C1-C4alkyl, R₁₂ is the same C1-C4 alkyl group as R₁₁, or R₁₁ and R₁₂ togetherform cyclopentane or cyclohexane, and R₁₃ is selected phenanthryloptionally substituted from 1 to 5 times with C₃ -C₇ secondary alkyl orC₄ -C₇ tertiary alkyl groups. The position of alkyl substituents on thearyl group is not critical; for example, phenyl can be substituted atpositions 1-6, naphthyl from positions 1-8, anthryl from positions 1-10,and phenanthryl from positions 1-10 substituted from 1 to 5 times withC1-C4 alkyl groups. It is understood that the oxygen atom illustrated inXVIII links the chiral auxiliary to the carbonyl carbon of compound XIIIand is included in the Formula XVIII to indicate the preferred bondingposition of the cyclic alkyl group that carbonyl carbon. In a morepreferred chiral auxiliary, R₁₁ and R₁₂ are both methyl or ethyl, andR₁₃ is phenyl.

In many instances it will be desirable that compound XIV has thestereochemical orientation of Formula (XIVa). ##STR14## In suchinstances, R₈ should be an optically auxiliary that will permit only theformation of diastereomers of compound XIV having this orientation. Asused herein, an "optically pure" compound is one which contains at least99 percent of one enantiomer of that compound. Preferred chiralauxiliaries for forming the diastereomers of Formula XIVa are as shownin Formula XVIIIa ##STR15## wherein R, R₁₁,R₁₂, and R₁₃ are as definedfor Formula VIII. As above, the oxygen atom of compound XVIIIa isincluded to show bonding position on the cyclic alkyl group andstereochemical orientation of the substituents thereon.

Scheme D proceeds in the same manner as Scheme C through the synthesisof compound X. At that point compound X is dehalogenated with a base ofthe formula A⁺ B⁻, wherein A⁺ is an inorganic cation, and B⁻ is anorganic anion, to form an intermediate, then reacting that intermediatewith an α-ketoester of Formula XIII to form a compound of Formula XIV.

The base A⁺ B⁻ can be any combination of an inorganic cation and anorganic anion which will remove Z from compound X to form a reactivecarbanion intermediate. Exemplary inorganic cations include sodium,potassium, and lithium, with lithium being more preferred. The organicanion can be any anion which is sufficiently basic to remove substituentZ from compound X but is insufficiently strong to remove substituent Yfrom compound X. Exemplary organic anions include propyl, n-butyl,t-butyl, phenyl, and n-pentyl, with n-butyl being preferred.

The reaction step in which Z is removed from compound X can be carriedout through the use of standard conditions for removing halogens fromaromatic compounds. Preferably, this step is carried out in an inertatmosphere, such as argon or nitrogen, and in an aprotic solvent, suchas tetrahydrofuran, diethyl ether, dimethoxyethane, and toluene, withtetrahydrofuran being preferred. The reaction is preferably carried outat a reduced temperature, and more preferably is carried out at below 0°C.

The combination of the intermediate produced by reaction with base A⁺ B⁻and the α-ketoester of formula XIV can be carried out through the use ofstandard conditions for nucleophilic attack of an aromatic carbanion atan α-carbonyl carbon. Preferably, the reaction is carried out in anaprotic solvent, such as those listed above, with tetrahydrofuran beingpreferred, and is carried out at a reduced temperature, preferably below0° C. In a more preferred embodiment of the process, the reacting stepand the combining step are carried out in the same reaction vessel, i.e,in situ.

Proceeding stepwise through Scheme D, a compound of Formula XV can thenbe prepared by saponifying a compound of Formula XIV with a base to forman intermediate, then protonating the intermediate with aqueous acid.

The saponification step can be carried out under any conditions that areknown for saponifying esters to carboxylic acids. Preferably, thesaponifying base used is a mixture of an inorganic base, such as sodiumhydroxide or potassium hydroxide, and a relatively polar organicsolvent, such as ethanol. The protonating step can be carried out withany aqueous acid solution, such as hydrochloric or sulfuric acid, thatwill protonate the carboxylate anion resulting from saponification ofthe ester linkage of compound XIV.

Preferably, the process is carried out so that after the saponificationstep, but prior to the protonating step, the chiral auxiliary (R₈) canbe recovered in good yield for re-use. This can be performed by anymethod of recovery known to be suitable for compounds of this type.Preferably, the basic solution remaining from the saponification iswashed with a non-polar, aprotic solvent, such as dimethyl ether ordiethyl ether, which extracts the chiral auxiliary R₈ from solution.

The final step of Scheme D is the formation of Compound III from acompound of Formula XV. This process comprises the steps of reactingcompound of Formula XV with a halotrialkylsilane in the presence of analkyl or aryl amine to form an intermediate, then cyclizing theintermediate by hydrolysis of the reaction product in aqueous acid tocleave the ether linkage of R₆ and R₇, the ring forming spontaneouslyupon ether cleavage. A preferred halotrialkylsilane isiodotrimethylsilane. Exemplary amines are secondary and tertiary amines,with 1,8-diazabicyclo[5,4,0]undec-7-ene being preferred. The ethers canbe cleaved by conventional methods, such as those described above inScheme C for producing compound III from compound XII. The process ispreferably carried out in an aprotic solvent, such as acetonitrile,tetrahydrofuran, or diethylether. Also, the process is preferablyconducted so that the reacting step and the cyclizing step are carriedout in the same reaction vessel, i.e., in situ.

Alternatively, a compound of the Formula XV can be made by Scheme E froma compound of Formula X. Scheme E is shown below. ##STR16##

R, R₆, R 7, and R₈ are as given above for Scheme D. R₁₀ can be any aryl,alkyl, or alkyl aryl group which will cause the compound of Formula XVIIto recrystallize and separate from the undesired minor diasteomer. R₁₀is preferably selected from the group consisting of biphenyl, anthryl,phenanthryl, and phenyl, any of which can be substituted from 1 to 5times with C1-C4 alkyl groups. The position of alkyl substituents on thearyl group is not critical; for example, phenyl can be substituted atpositions 1-6, naphthyl from positions 1-8, anthryl from positions 1-10,and phenanthryl from positions 1-10 substituted from 1 to 5 times withC1-C4 alkyl groups. More preferably, R₁₀ is biphenyl. X is selected fromthe group consisting of chlorine, bromine, and iodine.

Scheme E represents a process comprising the steps of reacting acompound of Formula X with a base A⁺ B⁻ to form first intermediate,combining the intermediate with an o-ketoester containing a chiralauxiliary of Formula XIII to form a second intermediate, the alkoxide ofcompound XIV, then acylating this second intermediate with a compound ofFormula XVI to form a compound of Formula XVII.

This scheme differs from Scheme D only in that another acylation step isincluded for the formation of an additional ester linkage at thehydroxyl group attached to the chiral carbon at position 7. The purposeof the additional substituent R₁₀ is to form a compound that can beseparated easily from solution by recrystallization. Without this step,it can be difficult to separate the compound of Formula XIV from a minordiastereomer by-product of the reaction; this is problematic if, as isoften the case when chiral auxiliaries are used in synthetic reactions,a diastereomerically or optically pure product is desired. By includingin compound XVII the ester linking R₁₀ to compound XIV, the reactionproduct XVII can be purified by standard recrystallization methods, suchas precipitation from an organic solvent, to produce adiastereomerically pure compound XVII. As used herein,"diastereomerically pure" means that a compound sample comprises atleast 99 percent of one of at least two possible diastereomers. Thisdiastereomerically pure compound XVII can in turn be used to produce anoptically pure compound XV, which in turn can be used to produce anoptically pure compound III.

Scheme E proceeds in the manner described above in Scheme D for thepreparation of Compound XIV. Once compound XIV has been prepared, theacylation step can be carried out in any manner known for acylatingtertiary alcohols with acyl halides. In a preferred embodiment, R₁₀ isadded to a reaction mixture in which compound XIV has been prepared inits alkoxide form, so that the reaction proceeds in situ. The solventshould be an aprotic solvent, such as tetrahydrofuran, diethyl ether,dimethoxyethane, or toluene, with tetrahydrofuran being preferred.Preferably the reaction occurs in an inert atmosphere, such as underargon or nitrogen. The reaction product is separated from the reactionmixture, preferably by recrystallization, for use in subsequent steps.If an optically pure chiral axillary R₈ was used, the recrystallizedcompound XVII will contain only one disastereomer, the diastereomerhaving a stereochemical orientation of the substituents of the chiralcarbon 7 of compound XVII directed by the chiral auxiliary. A preferredorientation at chiral carbon atom 7 is shown in Formula XVIIa. ##STR17##which can be produced by use of an optically pure compound of FormulaXIIIa. Any further synthetic process that includes compound XVIIa willthen produce reaction products having the same stereochemicalorientation at chiral carbon 7.

From this point, Scheme E parallels Scheme D. Compound XVII issaponified with a base to form an intermediate, then the intermediate isprotonated to form a compound of Formula XV. As was true for thesaponifying step of Scheme D, this step of Scheme E can be carried outwith any base that will cleave the ester linkages bonding R₈ and R₁₀ tocompound XVII. Preferably, the base is a mixture of a relatively polarorganic solvent, such as ethanol, and an inorganic aqueous base, such assodium hydroxide. After the saponifying base cleaves both ester linkagespresent in compound XVII to form the carboxylate and alkoxide form ofthe compound, the protonating acid then protonates these functionalgroups to form a compound of Formula XV. As in Scheme D, the chiralauxiliary can be recovered after saponification for re-use by nonpolarsolvent washing or some other suitable technique.

The final step of Scheme E is the cyclizing of compound XV to compoundIII. The same reaction conditions listed above for Scheme D are suitablehere. As indicated above, the compound can be made in an optically pureform by using an optically pure chiral auxiliary R₈ in Scheme E; apreferred stereochemical orientation is shown in Formula IIIa, ##STR18##which can be made from the diastereomerically pure form of compoundXVIIa after saponification to an optically pure form of compound XVa.

Specific examples of compounds which may be prepared by the method ofthe present invention include 9-methoxy-camptothecin,9-hydroxy-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin,10-hydroxycamptothecin, 10-nitro-camptothecin, 10-aminocamptothecin,10-chloro-camptothecin, 10-methylcamptothecin, 11-methoxy-camptothecin,11-hydroxycamptothecin, 11-nitro-camptothecin, 11-aminocamptothecin,11-formyl-camptothecin, 11-cyanocamptothecin, 12-methoxy-camptothecin,12-hydroxycamptothecin, 12-nitro-camptothecin,10,11-dihydroxycamptothecin, 10,11-dimethoxy-camptothecin,7-methyl-10-fluoro-camptothecin, 7-methyl-10-chlorocamptothecin,7-methyl-9,12-dimethoxy-camptothecin, 9,10,11-trimethoxy-camptothecin,10,11-methylenedioxycamptothecin and9,10,11,12-tetramethyl-camptothecin.

Compounds of Formula I have antitumor and antileukemic activity.Additionally, compounds of Formula I wherein R₁ is halo are useful asintermediates for, among other things, making compounds of Formula Iwherein R₁ is loweralkyl.

Those skilled in the art will appreciate that additional changes can bemade in the compounds of Formula I (see, for examples, J. Cai and C.Hutchinson, supra), which changes will not adversely affect the newprocesses disclosed herein and do not depart from the concept of thepresent invention.

In the Examples which follow, "mg" means milligrams, "g" means grams,"M" means Molar, mL means millimeter(s), "mmol" means millimole(s), "Bu"means butyl, "THF" means tetrahydrofuran, "h" means hours, "min" meansminutes, "C" means Centigrade, "p.s.i." means pounds per square inch,"DMF" means dimethylformamide, "TLC" means thin layer chromatography,and "PLC" means preparative thin layer chromatography.

EXAMPLE 1 6-Chloro-2-methoxy-3-pyridinecarboxaldehyde

To a solution of tert-butyllithium (1.7 M in pentane, 48.5 mL, 83.0mmol) in 150 mL of THF at -78° C. was added 6-chloro-2-methoxypyridine(8.94 mL, 75.0 mmol) over 5 min. The reaction mixture was stirred at-78° C. for 1 h, then dimethylformamide (7.55 mL, 97 mmol) was added andthe mixture was stirred at this temperature for 1.5 h. After theaddition of glacial acetic acid (8.6 mL, 150 mmol), the reaction mixturewas allowed to warm to room temperature over a 30- min period, thendiluted with ether (200 mL). The organic phase was washed with saturatedaqueous NaHCO₃ (100 mL) and brine (100 mL), and was dried over MgSO₄.Concentration afforded the crude product as a light yellow solid whichwas recrystallized from hexanes to give 9.6 g (75%) of6-chloro-2-methoxy-3-pyridinecarboxaldehyde as a white solid: mp 80°-81°C. (mp 62°-64° C.) (See Dainter, R. S.; Suschitzky, H.; Wakefield, B.J.Tetrahedron Lett. 1984, 25, 5693.). ¹ H NMR (300 MHz, CDCl₃) δ 10.31(s,1H), 8.07 (d, IH, J=9 Hz), 7.03 (d, IH, J=9 Hz), 4.09 (s, 3H); IR(nujol) 1685, 1580, 1565, 1270, 1140, 1090, 1005, 905, 820, 755 cm⁻¹.

EXAMPLE 2 6-Chloro-4-iodo-2-methoxy-3-pyridinecarboxaldehyde

To a solution of N,N,N'-trimethylethylenediamine (2.46 mL, 19.23 mmol)in 15 mL of 1,2-dimethoxyethane at -23° C. was added n-BuLi (9.22 mL, 3019.23 mmol), and the solution was stirred at -23° C. for 20 min. Themixture was transferred using a doubletipped needle to a solution of6-chloro-2-methoxy-3-pyridinecarboxaldehyde (3.0 g, 17.5 mmol) in 40 mLof 1,2-dimethoxyethane at -23° C. After stirring for 15 min, n-BuLi(12.6 mL, 26.2 mmol) was added and the dark mixture was stirred anadditional 2 h at -23° C. The solution was transferred using adouble-tipped needle to a solution of iodine (8.04 g, 31.7 mmol) in 40mL of 1,2-dimethoxyethane at -78° C. After stirring at -78° C. for 30min, the cooling bath was removed and the reaction mixture was allowedto warm for 20 min, then quenched with water. The mixture was extractedwith ether (2×30 mL) and the combined organic layers were washedsuccessively with 30-mL portions of 10% aqueous Na₂ S₂ O₃, water andbrine, and dried over MgSO₄. Concentration afforded 4.62 g (89%) ofcrude product to which was added 50 mL of hexanes. The mixture wasstirred and allowed to stand at 5° C. overnight. Filtration gave 2.67 gof 6-chloro-4-iodo-2-methoxy-3-pyridinecarboxaldehyde as a yellow solid:mp 120°-124° C. Concentration of the hexane washings and purification ofthe residue by radial preparative thin-layer chromatography (silica gel,5% ethyl acetate/hexanes) gave an additional 1.41 g of product (mg120°-124° C.), raising the total yield of the compound to 78%.Recrystallization from hexanes gave an analytical sample as a brightyellow solid: mp 129°-130° C. ¹ H NMR (300 MHz, CDCl₃) δ 10.16 (s, 1H),7.59 (s, 1H), 4.07 (s, 1H); IR (nujol) 1690, 1350, 1260, 1095, 1010,900, 840 cm⁻¹.

EXAMPLE 3 2-Chloro-4-iodo-6-methoxy-5-(methoxymethyl)pyridine

To a mixture of 6-chloro-4-iodo-2-methoxy-3-pyridinecarboxaldehyde (1.07g, 3.60 mmol), triethylsilane (0.86 mL, 5.40 mmol) and methanol (0.43mL, 10.6 mmol) at 0° C. was added trifluoroacetic acid (2.2 mL, 28.6mmol), and the resulting solution was stirred at 25° C. for 14 h. Afterdilution with ether (30 mL), saturated NaHCO₃ was added until theaqueous phase was rendered basic. The aqueous layer was extracted withether (10 mL), and the combined ether layers were washed with water (10mL) and brine (10 mL), and dried (Na₂ SO₄). Concentration gave the crudeproduct which was purified by radial PLC (silica gel, 5% ethylacetate/hexanes) to afford2-chloro-4-iodo-6-methoxy-5-(methoxymethyl)pyridine as a white solid(1.05 g, 93%): mp 69°-72° C. Recrystallization from hexanes provided ananalytical sample: mp 74°-75° C. ¹ H NMR (300 MHz, CDCl₃) δ 7.40 (S,1H), 4.53 (s, 2H), 3.96 (s, 3H), 3.42 (s, 3H); IR (nujol) 1550, 1300,1115, 1090, 1020, 940, 905, 830, 720 cm⁻¹.

EXAMPLE 4 Ethyl2-hydroxy-2-(6'-chloro-2'-methoxy-3'-methoxymethyl-4'-pyridyl)butyrate

To a solution of 2-chloro-4-iodo-6-methoxy-5-(methoxymethyl)pyridine(2.28 g, 7.30 mmol) in 50 mL of THF at -90° C. was added n-BuLi (3.46mL, 8.03 mmol) over 5 min and the resulting solution was stirred at -90°C. for 30 min. Ethyl α-ketobutyrate (1.25 mL, 9.45 mmol) was added, thereaction mixture was stirred at -90° C. for 30 min, then allowed to warmat ambient for 20 min, and quenched with saturated NH₄ Cl. After removalof most of the solvent under reduced pressure, the residue was taken upin 40 mL of ether, washed with dilute NaHCO₃ (15 mL) and brine (15 mL),and was dried over MgSO₄. Evaporation of the solvent in vacuo andpurification of the residue by radial PLC (10% acetone/hexanes) affordedethyl-2-hydroxy-2-(6'-chloro-2'-methoxy-3'-methoxymethyl-4'-pyridyl)butyrate(1.53 g, 66%) as a light yellow, viscous oil. ¹ H NMR (300 MHz, CDCl₃) δ7.07 (s, 1H), 4.75 (d, 1H, J=12 Hz), 4.47 (d, 1H, J=12 Hz), 4.24 (q, 1H,J=6 Hz), 4.17 (q, 1H, J=6 Hz), 3.96 (s, 3H), 3.37 (s, 3H), 2.16 (m, 2H),1.24 (t, 3H, J=6 Hz); IR (film) 3400, 1735, 1580, 1555, 1305, 1235,1130, 1090, 1020, 905, 830, 730 cm⁻¹.

EXAMPLE 59-Chloro-7-oxopyrido[5,4-cl-2-oxo-3-ethyl-3-hydroxy-3,6-dihydropyran

To a stirred mixture of the hydroxy ester prepared in Example 4 above(1.53 g, 4.82 mmol) and sodium iodide (2.89 g, 19.3 mmol) in dry CH₃ CN(35 mL) at 25° C. was added dropwise chlorotrimethylsilane (2.45 mL,19.3 mmol). The resulting solution was heated at reflux for 4 h, thesolvent was removed under reduced pressure, and 100 mL of 5N HCl wasadded to the residue. After heating at a gentle reflux for 4 h, themixture was stirred at 25° C. overnight, then extracted with six 30-mLportions of CHCl₃ containing 5% CH₃ OH. The combined organic extractswere washed with 40 mL of half-saturated NaCl containing Na₂ S₂ O₃,followed by 40 mL of saturated NaCl. After drying over Na₂ SO₄, thesolvent was removed under reduced pressure and the residue was purifiedby radial PLC (silica gel, 5% CH₃ OH/CHCl₃ ) to give9-chloro-7-oxopyrido[5,4-c]-2-oxo-3-ethyl-3-hydroxy-3,6-dihydropyran(743 mg, 63%) as an off-white solid: mp 205°-207° C. Recrystallizationfrom CHCl₃ /CH₃ OH gave an analytically pure sample as a white solid: mp207°-208° C. ¹ H NMR (300 MHz, CDCl₃ DMSO-d6) δ 6.79 (s, 1H), 5.49 (d,1H, J=15 Hz), 5.13 (d, 1H, J=15 Hz), 1.78 (q, 2H, J=6 Hz), 0.93 (t, 3H,J=9 Hz), IR (nujol) 3450, 1740, 1640, 1600, 1560, 1320, 1225, 1140,1035, 995, 940 cm⁻¹.

EXAMPLE 6 7-Oxopyrido[5,4-c]-2-oxo-3-hydroxy-3-hydroxy-3,6-dihydropyran

A mixture of the chloropyridone prepared in Example 5 above (400 mg,1.64 mmol) and sodium acetate (400 mg, 4.86 mmol) in 25 mL of ethanolwas hydrogenated over 10% Pd/C (100 mg) at 42 psi for 4 h. The mixturewas filtered through celite and the solids were washed with CH₃ OH. Thefiltrate was concentrated and the residue was purified by radial PLC(silica gel, 5% CH₃ OH/CHCl₃) to give the pure product (256 mg, 75%) asa white solid: mp 230°-232° C. (dec.). Recrystallization from CHCl₃ /CH₃OH afforded an analytical sample: mp 232° C. (dec.). ¹ H NMR (300 MHz,CHCl₃ /DMSO-d6) δ 7.30 (d, 1H, J=6 Hz), 6.49 (d, 1H, J=6 Hz), 5.42 (d,1H, J=18 Hz), 5.12 (d, 1H, J=18 Hz), 1.79 (m, 2H), 0.91 (t, 3H, J=6 Hz);IR (nujol) 3300, 1750, 1640, 1620, 1555, 1065, 1030, 995, 805 cm⁻¹.

EXAMPLE 7 2-Chloro-3-quinolinecarboxaldehyde

To a solution of 0.46 mL (3.30 mmol) of diisopropylamine in 8 mL of THFat 0° C. was added 1.53 mL (3.30 mmol) of n-BuLi dropwise. After 20 minthe solution was cooled to -78° C. and 2-chloroquinoline (491 mg, 3.0mmol) was added neat. The mixture was stirred at -78° C. for 30 min,then dimethylformamide (0.39 mL, 5.04 mmol) was added dropwise and thereaction mixture was stirred an additional 30 min at this temperature.After quenching at -78° C. with glacial acetic acid (1 mL), the mixturewas warmed to room temperature and diluted with ether (30 mL). Theorganic phase was washed with saturated NaHCO₃ solution (10 mL) andbrine (10 mL), and was dried over MgSO₄. Concentration afforded2-chloro-3-quinolinecarboxaldehyde (530 mg, 92%) as a light yellow solid(mp 145°-149 ° C.), which was used directly in the next step withoutfurther purification. Recrystallization from ethyl acetate afforded thepure compound as light yellow needles: mp 49°-150° C. (mp 148°-149° C.reported in Meth-Cohn, O.; Narhe, B.; Tarnowski, B. J. Chem. Soc. PerkinTrans. I 1981, 1520.). ¹ H NMR (300 MHz, CDCl₃) δ 10.57 (s, 1H), 8.77(s, 1H), 8.08 (d, 1H, J=9 Hz), 8.0 (d, 1H, J=9 Hz), 7.90 (t, 1H, J=9Hz), 7.67 (t, 1H, J=9 Hz); IR (nujol) 1685, 1575, 1045, 760, 745 cm⁻¹.

EXAMPLE 8 Preparation of 2-Chloro-3-quinolinecarboxaldehyde fromacetanilide

Following a literature procedure (see MethCohn, O.; Narhe, B.;Tarnowski, B. J. Chem. Soc. Perkin Trans. I 1981, 1520), a phosphorusoxychloride (24.0 mL, 260 mmol) was added dropwise to an ice-coldsolution of dimethylformamide (7.20 mL, 93.0 mmol) and the deep-redsolution was stirred at 0° C. for 30 min. Acetanilide (5.0 g, 37.0 mmol)was added neat and the mixture was stirred at 0° C. for 30 min., thenheated at 75° C. for 16 h. The cooled mixture was poured into 250 mL ofice-water and stirred at 0°-5° C. for 30 min. The product was filtered,washed with water, and recrystallized from ethyl acetate to give 5.2 g(74%) of 2-chloro-3-quinoline-carboxaldehyde as a light yellow solid: mp147°-149° C.

EXAMPLE 9 2-Iodo-3-quinolinecarboxaldehyde

A mixture of the aldehyde prepared in accordance with Example 7 or 8above (5.0 g, 26.2 mmol), sodium iodide (10.0 g, 66 7 mmol) andconcentrated HCl (1 mL) in 100 mL of CH₃ CN was heated at reflux for 4.5h. After removal of most of the solvent in vacuo, aqueous Na₂ CO₃ wasadded until the mixture was basic, and the product was filtered andwashed with water. The crude product was recrystallized from 95% ethanolto give 6.51 g (88%) of 2-iodo-3-quinolinecarboxaldehyde as off-whitefluffy needles: mp 156°-157° C. (mp 150°-152° C. reported in Meth-Cohn,O.; Narhe, B.; Tranowski, B.; Hayes, R.; Keyzad, A.; Rhavati, S.;Robinson, A. J. Chem. Soc. Perkin Trans. I 1981, 2509). ¹ H NMR (300MHz, CDCl₃) δ 10.29 (s, 1H), 8.57 (s, 1H), 8.12 (d, 1H, J= 9 Hz), 7.98(d, 1H, J=9 Hz) 7.88 (t, 1H, J=9 Hz), 7.68 (t, 1H, J=9 Hz); IR (nujol)1680, 1610, 1570, 1555, 1315, 1020, 1005, 750, 740 cm⁻¹.

EXAMPLE 10 3-Hydroxymethyl-2-iodoquinoline

To a stirred solution of 2-iodo-3-quinolinecarboxaldehyde (595 mg, 2.10mmol) in 40 mL of CH₃ OH at 0° C. was added NaBH₄ (86 mg, 2.31 mmol),and the mixture was stirred at 0° C. for 30 min. After concentrating themixture to approximately one-half of its original volume, water (30 mL)was added and the mixture was allowed to stand at 5° C. overnight. Thesolids were filtered and the crude product (570) mg, 95%) wasrecrystallized from methanol to give 3-hydroxymethyl-2-iodoquinoline(505 mg, 84%) as colorless needles: mp 189°-190° C. ¹ H NMR (300 MHz,CDCl₃) δ 8.19 (s, 1H), 7.99 (d, 1H, J=9 Hz), 7.87 (d, 1H, J=9 Hz), 7.68(m, 1H), 7.58 (t, 1H, J=9 Hz), 5.45 (t, 1H, J=6 Hz), 4.66 (d, 2H, J=6Hz); IR (nujol) 3350, 1580, 1320, 1125, 1060, 995, 755, 720, cm⁻¹.

EXAMPLE 11 3-Chloromethyl-2-iodoquinoline

To a stirred mixture of 3-hydroxymethyl-2-iodoquinoline prepared inaccordance with Example 10 above (350 mg, 1.23 mmol) andtriphenylphosphine (483 mg, 1.84 mmol) in 10 mL of dry DMF at -23° C.was added N-chlorosuccinimide (246 mq, 1.84 mmol), and the mixture wasstirred for 1 h at -23° C. After the addition of 40 mL of dilute aqueousNaHCO₃, the mixture was extracted with ethyl acetate (20 mL) and thenether (2×15 mL). The combined organic extracts were washed successivelywith 20-mL portions of dilute NaHCO₃, water and brine, and were driedover MgSO₄. Concentration and purification of the residue by radial PLC(silica gel, 10% ethyl acetate/hexanes) afforded 312 mg (84%) of3-chloromethyl- 2-iodoquinoline as a white crystalline solid: mp138°-140° C. Recrystallization from hexanes afforded an analyticalsample as colorless needles: mp 139°-140° C. ¹ H NMR (300 MHz, CDCl₃) δ8.17 (s, 1H), 8.07 (d, 1H, J=9 Hz), 7.84 (d, 1H, J=9 Hz), 7.75 (t, 1H,J=9 Hz), 7.62 (t, 1H, J=9 Hz), 4.80 (s, 1H); IR (nujol) 1585, 1555,1260, 1010, 780, 755, 710 cm⁻¹.

EXAMPLE 128-(21-Iodo-3'-quinolylmethyl)-7-oxopyrido[5,4-cl-2-oxo-3-ethyl-3-hydroxy-3,6-dihydropyran

To a solution containing 45 mg (0.40 mmol) of potassium tert-butoxide in4 mL of dry isopropyl alcohol at 25° C. was added 55 mg (0.26 mmol) of7-oxopyrido[5,4-c]-2-oxo-3-ethyl-3-hydroxy-3, 6-dihydropyran prepared inaccordance with Example 6 above and the mixture was stirred at 25° C.for 30 min. A solution of 3-chloromethyl-2-iodoquinoline prepared inaccordance with Example 11 above (104 mg, 0.35 mmol) in 1 mL of CH₃ OHwas added dropwise to the white suspension, and the resulting solutionwas heated at 75° C. for 24 h. After quenching the reaction mixture withsaturated NH₄ Cl, the solvents were removed under reduced pressure, andthe residue was taken up in CH₂ Cl₂ (20 mL) and washed with brine (2×10mL). Concentration and purification of the residue by radial PLC (2% CH₃OH/CHCl₃) gave the a white solid: mp 171°-174° C. (dec.).Recrystallization from ethyl acetate/hexanes afforded an analyticalsample: mp 174° C. (dec.). ¹ H NMR (300 MHz, CDCl₃) δ 8.05 (d, 1H, J=9Hz), 7.70-7.80 (m, 3H), 7.55-7.61 (m, 2H), 6.61 (d, 1H, J=9 Hz), 5.63(d, 1H, J=15 Hz), 5.43 (d, 1H, J=15 Hz), 5.27 (d, 1H, J=9 Hz), 5.22 (d,1H, J=9 Hz); IR (nujol) 3350, 1750, 1650, 1590, 1565, 1160, 1140, 1000,750 cm⁻¹.

EXAMPLE 13 (±)-Camptothecin

A mixture of8-(2'-iodo-3'-quinolylmethyl)-7-oxopyrido[5,4-c]-2-oxo-3-ethyl-3-hydroxy-3,6-dihydropyranprepared in accordance with Example 12 above (76 mg, 0.16 mmol), K₂ CO₃(44 mg, 0.32 mmol), tetrabutylammonium bromide (52 mg, 0.16 mmol) andPd(OAc)₂ (3.6 mg, 0.016 mmol) in 15 mL of dry acetonitrile under argonwas heated at 90° C. for 5 h. TLC analysis of the reaction mixtureshowed a single spot which was highly U.V. active. The mixture wascooled, concentrated, and the residue was taken up in 30 mL of CHCl₃containing 10% CH₃ OH. This was washed with two 10-mL portions ofsaturated aqueous NH₄ Cl. The organic layer was dried over Na₂ SO₄ andconcentrated. The dark residue was subjected to radial PLC (silica gel,4% CH₃ OH/CHCl₃), to give 17 mg of an orange solid which was shown byNMR analysis to be a mixture of impure (±)-camptothecin andtetrabutylammonium bromide. The aqueous washings were filtered to give ayellow solid which was purified by radial PLC (silica gel, 4% CH₃OH/CHCl₃) to afford (±)-camptothecin (26 mg, 47%) as a yellow solid: mp275°-277° C. (mp 275°-277° C. reported in Volman, R.; Danishefsky, S.;Eggler, J.; Soloman, D. M., J. Am. Chem. Soc. 1971, 93, 4074.).

EXAMPLE 14 Synthesis of(1R,4S,5R)-8-ohenvlmenthvl-(S)-2-(4-phenylbenzoyloxy)-2-(6'-chloro-2'-methoxy-3'-methoxymethyl-4'-pvridyl)butyrate

n-BuLi (1.86 M, 2.72 mL, 5.05 mmol) was added to a vigorously stirredsolution of 6-chloro-4-iodo-3-methoxymethyl-2-methoxypyridine (1.51 g,4.81 mmol) in 30 mL of THF at -78° C. under Ar, and the mixture wasstirred for 1 min. A solution of (-)-8-phenylmenthyl 2-ketobutyrate(1.60 g, 5.29 mmol) in 3 mL of THF was added. The reaction mixture wasstirred at -78° C. for 1 h after whioh a solution of 4-biphenylcarbonylchloride (1.34 g, 7.22 mmol) in 3 mL of THF was added. The cooling bathwas removed and the reaction mixture was allowed to warm to roomtemperature. Stirring was continued at room temperature for 36 h. Thesolvent was removed in vacuo and the residue was dissolved in 125 mL ofCH₂ Cl₂. The mixture was washed with 40-mL portions of 10% aqueousNaHCO₃, water and brine. The organic layer was dried over MgSO₄ andconcentrated. The residue was dissolved in 50 mL of ether and filteredthrough a short plug of silica gel. Concentration produced a lightyellow solid which was dissolved in 30 mL of boiling petroleum ether (bp37°-55° C). The product precipitated upon standing at room temperatureovernight. After cooling to 0° C. for several hours, the product wasfiltered and washed with a minimum of petroleum ether to produce 1.97 g(60% yield) of (1R,4S,5R)-8-phenylmenthyl-(S)-2-(4-phenylbenzoyloxy)-2-(6'-chloro-2'-methoxy-3'-methoxymethyl-4'-pyridyl)butyrateas a white solid (mp 100°-103° C.). ¹ H NMR: (300 MHz, CDCl₃) δ 8.22 (d,2 H, J=7 Hz), 7.05-7.80 (m, 13 H), 4.85 (m, 1 H), 4.50 (s, 2 H) 3.97 (s,3 H), 3.16 (s, 3 H), 2.61 (m, 1 H) 0.55-2.35 (m, 21 H); ¹ H NMR:(1R,4S,5R)-8-phenylmenthyl(R)-2-(4-phenylbenzoyloxy)-2-(6'-chloro-2'-methoxy-3'-methoxymethyl-4'-pyridyl)butyrate(minor diastereomer): (300 MHz, CDCl₃), δ 8.22 (d, 2 H, J=7 Hz)7.05-7.80 (m, 13 H), 4.85 (m, 1 H), 4.62 (d, 1 H, J=9 Hz), 4.35 (d, 1 H,J=9 Hz), 3.90 (s, 3 H), 2.98 (s, 3 H), 2.62 (m, 1 H), 0.6-2.10 (m, 21H).

EXAMPLE 15 Synthesis of(S)-2-hydroxy-2-(6'chloro-2'-methoxy-3'methoxymethyl-4'pyridyl)butyricacid by Saponification of (1R,4S,5R)-8-phenylmenthyl(S)-2-(4-phenylbenzoyloxy)-2-(6'-chloro-2'-methoxy-3'-methoxymethyl-4'-pyridyl)butyrate

A solution of(1R,4S,5R)-8-phenylmenthyl-(S)-2-(4-phenylbenzoyloxy)-2-(6'-chloro-2'-methoxy-3'-methoxymethyl-4'-pyridyl)butyrate(201 mg, 0.294 mmol) in 6 mL of a 1:1 ethanol/2N NaOH was heated at85°-90° C. for 12 h. Most of the ethanol was removed under reducedpressure and the residue was diluted with water (3 mL) and extractedwith ether (3×4-mL). It is noteworthy that the chiral auxiliary((-)8-phenylmenthol) was recovered in quantitative yield afterevaporation of the ether extracts. The aqueous layer was acidified to apH of 1 with 20% HCl and extracted with CH₂ Cl₂ (3×5-mL). The combinedorganic layers were washed with water (2×5-mL) and brine (5 mL) and weredried over anhydrous Na₂ SO₄. Concentration produced 142 mg of crudeproduct which upon ¹ H NMR analysis was determined to be a 1:1 mixtureof(S)-2-hydroxy-2-(6'chloro-2'-methoxy-3'methoxymethyl-4'pyridyl)butyricacid and 4-biphenylcarboxylic acid. To this crude product was added 20mL of hexanes, and, after bringing the solution to a boil, ethyl acetatewas added dropwise until a clear homogeneous solution resulted. Afterstanding at 25° overnight, the mixture was filtered, the solids werediscarded, and the filtrate was concentrated to afford a colorlesssemi-solid. This process was repeated using 5 mL of hexanes and 2-3drops of ethyl acetate to remove additional 4-biphenylcarboxylic acid.After concentration of the filtrate, 45 mg of(S)-2-hydroxy-2-(6'chloro-2'-methoxy-3'methoxymethyl-4-pyridyl)butyricacid (76% yield) was obtained as a colorless viscous oil. ¹ H NMR 300MHz (CDCl₃) δ 7.13 (s, 1 H), 4.81 (d, 1 H, J=13 Hz), 4.55 (d, 1 H, J=13Hz), 3.96 (s, 3 H), 3.39 (s, H), 2.19 (m, 2 H), 1.01 (t, 3 H, J=7 Hz).This material was usable in subsequent synthetic steps requiring anoptically pure compound without further purification.

The foregoing examples are illustrative of the present invention, andare not to be construed as limiting thereof. The invention is defined bythe following claims, with equivalents of the claims to be includedtherein.

That which is claimed is:
 1. An optically pure compound of the formula##STR19## wherein R is lower alkyl, and Y is H, F or Cl.
 2. A compoundaccording to claim 1, wherein R is methyl, ethyl, propyl, or butyl.
 3. Acompound according to claim 1, wherein Y is Cl or F.
 4. A compoundaccording to claim 1, wherein Y is Cl.
 5. A compound according to claim4, wherein R is methyl, ethyl, propyl, or butyl.
 6. A compound accordingto claim 4, wherein R is methyl.